CXCR5 is a non-promiscuous chemokine receptor belonging to the family of G-Coupled Protein receptors (GPCRs). Specifically, the CXCR5 receptor interacts with its CXCL13 ligand—which is constitutively expressed on stromal cells, such as follicular dendritic cells, and in lymphoid tissues. The CXCL13 ligand specifically attracts B cells and a small subset of T cells called B helper follicular T cells (TFH). When the CXCR5/CXCL13 interaction is blocked by an antagonist, patients with Rheumatoid Arthritis (RA) and other autoimmune or inflammatory diseases in which the up-regulation of CXCR5 and/or its ligand CXCL13 are responsible for the pathogenesis or exacerbation of the disease, can be treated. While B cell depletion therapy with anti-CD20 monoclonal antibody (Rituximab) has shown as efficacious in the treatment of RA, blocking of B cells, such as CXCR5-expressing cells, is known to be of therapeutic benefit in experimental murine models of arthritis.
Furthermore, CXCR5 and/or CXCL13 is known to be up-regulated in patients with Rheumatoid Arthritis [Arthritis Res Ther. 2005; 7(2):R217-29. Epub 2004 Dec. 16.], Sjogren's syndrome [Arthritis Rheum. 2001 November; 44(11):2633-41.], myasthenia gravis [J Neuroimmunol. 2005 Dec. 30; 170(1-2):172-8. Epub 2005 Oct. 7] and multiple sclerosis [Brain. 2006 January; 129(Pt 1):200-11. Epub 2005 Nov. 9]. A linkage between CXCR5 and pancreatic carcinoma [Cancer Res. 2006 Oct. 1; 66(19):9576-82.] is also known. By blocking the receptor/ligand interaction with a CXCR5 antagonist, therapeutic benefits can be realized in the diseases mentioned above, and in other diseases in which B cell infiltration (or other lymphocyte subsets expressing the CXCR5 receptor) is responsible for the pathogenesis of the disease [Front Biosci. 2007 Jan. 1; 12:2194-2006, J Rheumatol Suppl. 2006 May; 77:3-11].
Infiltration of lymphocytes into tertiary ectopic germinal centers (GCs) is known to correlate well with increased disease severity and tolerance breakdown. By using in vivo murine models, such as CXCR5−/− and CXCL13−/− mice, for example, the absence of either the receptor or the ligand, results in an altered GC fine architecture caused by changed T and B cell localization. These mice are known to be protected against developing severe collagen-induced arthritis (CIA). Thus, since CXCR5 is selectively expressed on mature B cells, which are linked to the pathogenesis of RA, an antagonist that capable of blocking this receptor can modulate the arthritogenic response in affected individuals. Presently, Rheumatoid arthritis treatment with anti-CD20 antibodies has shown to be clinically effective; such as with patients on B cell directed therapy, who have shown long-lasting improvements in clinical signs and symptoms. The selective targeting of CXCR5, which is only expressed on mature B cells and B helper T cells is, therefore, not expected to affect B cell development or immuno-compromise the patient
Thus, an unmet need exists for CXCR5 antagonists for treatment of Rheumatoid Arthritis and other inflammatory, autoimmune diseases and cancers caused by the interaction of B cells expressing CXCR5 in response to CXCL13 expression.